The rockefeller university

Interferon-gamma (IFN1) is critical for immunity against intra-macrophagic pathogens, signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway to induce a tyrosinephosphorylation cascade that ensures a potent immune response. Excessive JAK-STAT signaling can drive hyperinflammation and autoimmunity; thus, signaling is tightly and selectively regulated by the IFN1-induci-ble protein, suppressor of cytokine signaling 1 (SOCS1). SOCS1 inhibits signaling by directly blocking JAK kinase activity. Here, we identified a SOCS1-interacting partner, ankyrin repeat and pleckstrin homology domain 2 (ARAP2), that fine-tunes SOCS1 function. We report that tyrosine 415 in ARAP2 binds the SOCS1-Src homology 2 (SH2) domain and limits the ability of SOCS1 to inhibit IFN1 signaling. Our findings show that ARAP2 promotes the IFN1 response through a phosphorylation-dependent interaction with the negative regulator SOCS1, and this exacerbates inflammation in a mouse model of influenza virus infection.

The COVID-19 pandemic has increased public reliance on natural treatments, particularly in regions with strong cultural ties to herbal medicine or limited access to conventional healthcare. Globally, surveys have reported heightened use of plant-based remedies and dietary supplements, perceived as safe and effective. In Israel, this trend was evident within an integrative healthcare system that combines conventional and complementary medicine. The public demonstrated significant interest in herbal remedies and supplements to boost immunity and manage pandemic-induced stress. Natural compounds with anti-inflammatory and antiviral properties offer potential pharmacological benefits, warranting clinical investigation. However, restrictive trial criteria hinder broader applicability of findings. To address this gap, we evaluated the effects of bioactive dietary supplements on COVID-19 severity and duration through an online survey. Among respondents, Boswellia emerged as the most popular supplement. Disease duration in Boswellia users was significantly reduced (11.8 +/- 7.1 days) compared to untreated cases or those taking other supplements (18.0 +/- 9.7 days). Known as frankincense, Boswellia's gum resin has traditionally been used for its anti-inflammatory properties. Its bioactive compounds, boswellic acids and incensole acetate, inhibit cytokines like TNF alpha, IL-1 beta, and IL-6, implicated in COVID-19-related cytokine storms and ARDS. Preliminary clinical and laboratory studies suggest Boswellia's potential as an anti-inflammatory and antiviral agent. Laboratory experiments corroborated these findings, demonstrating that cultures infected with 229e virus, as measured by qPCR. Boswellia extracts also decreased viral RNA levels by up to 75% without adverse effects on cell viability and inhibited TMPRSS2 activity, a key protease for viral entry. These findings underscore Boswellia's therapeutic potential, combining anti-inflammatory and antiviral mechanisms, and support further investigation into its use as a complementary treatment for COVID-19.

Climate and land use change have increased human-wildlife interactions, potentially reducing wild species density and prompting behavioral adaptations to urbanized environments. It is still debated if behavioral responses are mainly the result of phenotypic plasticity or if they were driven by anthropic selective pressures, especially in small populations where genetic drift is strong. Our study focused on the small Apennine brown bear population (Ursus arctos marsicanus), which has coexisted with humans in Central Italy for millennia. We characterized genomic diversity and identified adaptation signals distinctive to this population by comparing newly generated and published whole-genome resequencing data from Apennine, Central European, and North American brown bears. Apennine brown bears exhibited reduced genomic diversity, higher inbreeding, and larger realized genetic load compared to other brown bears. We showed that Apennine brown bears possess a unique genomic diversity pattern including selective signatures at genes associated with reduced aggressiveness (eg DCC, SLC13A5). Within these genes, most of the newly discovered variants were located in noncoding regions and some of them were predicted to alter splicing factor binding sites, highlighting the contribution of noncoding variation in shaping complex phenotypes. Our results support the hypothesis that human-induced selection has promoted behavioral changes even in small- and long-isolated populations, reducing conflicts and contributing to the long-term persistence of a large mammal species and its coexistence with humans.

Anthracycline chemotherapy, widely used in cancer treatment, poses a significant risk of cardiotoxicity that results in functional decline. Current diagnostic methods poorly predict cardiotoxicity because they do not detect early damage that precedes dysfunction. Positron emission tomography (PET) is well suited to address this need when coupled with suitable imaging biomarkers. We used PET to evaluate cardiac molecular changes in male C57BL/6J mice exposed to doxorubicin (DOX). These mice initially developed cardiac atrophy, experienced functional deficits within 10 weeks of treatment, and developed cardiac fibrosis by 16 weeks. Elevated cardiac uptake of [68Ga]Ga-FAPI-04, a PET tracer targeting fibroblast activation protein alpha (FAP), was evident by 2 weeks and preceded the onset of functional deficits. Cardiac PET signal correlated with FAP expression and activity as well as other canonical indicators of cardiac remodeling. By contrast, cardiac uptake of [18F]DPA-714 and [18F]MFBG, which target translocator protein 18 kDa and the norepinephrine transporter, respectively, did not differ between the DOX animals and their controls. These findings identify FAP as an early imaging biomarker for DOX-induced cardiac remodeling in males and support the use of FAP PET imaging to detect some cancer patients at risk for treatment-related myocardial damage before cardiac function declines.

Cell movement and division are complex behaviors driven by a dynamic internal cytoskeleton. The molecular components and principles of cytoskeletal assembly are well studied, but less is known about cytoskeletal remodeling events, including how centrioles transition from ciliary base to centrosome. Here, we address this using the chytrid Rhizoclosmatium globosum, a zoosporic fungus that has centrioles and cilia, lost in most fungal lineages. Chytrids undergo reorganization of their microtubule cytoskeleton as they grow from zoospore to multinucleated coenocyte. We use evolutionary comparison, RNA-sequencing, and expansion microscopy to understand this reorganization and further develop this organism as a model for evolutionary cell biology. We find that when motile zoospores transition to sessile sporangia, cilia are retracted into the cytoplasm and degraded, while centrioles detach from the ciliary axoneme yet persist. During the mitotic cycles, short centrioles are associated with a centrosome-like microtubule-organizing center (MTOC) and a dense microtubule array at the spindle pole. After the mitotic cycles, centrioles elongate and form cilia, driven by transcription of genes associated with centriole maturation and ciliogenesis, and microtubule bundles are reorganized. Thus, in chytrids structural remodeling of the centriole is temporally coupled to specific changes in cytoskeletal organization over the coenocytic lifecycle.

Antiretroviral therapy suppresses HIV-1 infection but fails to eliminate a reservoir of intact latent proviruses that reside primarily in CD4+ T cells. The lack of precise understanding of the latent compartment has made it challenging to develop curative strategies for HIV-1 infection. Here we report on the properties of CD4+ T cell clones carrying intact latent proviruses, expanded in vitro from single cells obtained from the reservoir of people living with HIV-1. The latent proviruses in the clones were integrated into ZNF genes, nongenic satellite, and centromeric regions, frequently associated with latency. Despite their descent from single cells, only a fraction of the cells (0.4-14%) expressed relatively low levels of HIV-1 that did not measurably alter host gene transcriptome. Latency-reversing agents (LRAs) variably increased expression, but the effects were modest and clone and LRA specific. The results suggest that pharmacologic and immunologic approaches to clear the reservoir should be optimized to accommodate intra- and inter-clonal diversity.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas (CRISPR-associated) systems provide adaptive immunity against phage infection in prokaryotes using an RNA-guided complex that recognizes complementary foreign nucleic acids. Different types of CRISPR-Cas systems have been identified that differ in their mechanism of defense. Upon infection, type III CRISPR-Cas systems employ the Cas10 complex to find phage transcripts and synthesize cyclic oligo-adenylate (cOA) messengers. These ligands bind and activate CARF immune effectors that cause cell toxicity to prevent the completion of the viral lytic cycle. Here, we investigated two proteins containing an N-terminal haloacid dehalogenase (HAD) phosphatase domain followed by four predicted transmembrane helices and a C-terminal CARF domain. We named these proteins Chp for CRISPR-associated HAD phosphatase. We show that, in vivo, Chp localizes to the bacterial membrane and that its activation induces a growth arrest, leads to a depletion of ATP and IMP, and prevents phage propagation during the type III CRISPR-Cas response. In vitro, the CARF domain of Chp binds cyclic tetra-adenylates and the HAD phosphatase domain dephosphorylates dATP, ATP, and IMP. Our findings extend the range of molecular mechanisms employed by CARF effectors to defend prokaryotes against phage infection.

The female Aedes aegypti mosquito's remarkable ability to hunt humans and transmit pathogens relies on her unique biology. Here, we present the Aedes aegypti Mosquito Cell Atlas, a comprehensive single-nucleus RNA sequencing dataset of more than 367,000 nuclei from 19 dissected tissues of adult female and male Aedes aegypti, providing cellular-level resolution of mosquito biology. We identify novel cell types and expand our understanding of sensory neuron organization of chemoreceptors across all sensory tissues. Our analysis uncovers male-specific cells and sexually dimorphic gene expression in the antenna and brain. In female mosquitoes, we find that glial cells, rather than neurons, undergo the most extensive transcriptional changes in the brain following blood feeding. Our findings provide insights into the cellular basis of mosquito behavior and sexual dimorphism. The Aedes aegypti Mosquito Cell Atlas resource enables systematic investigation of cell-type-specific expression across all mosquito tissues.

Cancer cells require substantial metabolic adaptations to metastasize to distant organs, but the metabolites essential for successful colonization remain poorly defined. In this study, we used a mitochondrial metabolomics approach to compare primary and metastatic breast cancer cells. This analysis revealed accumulation of mitochondrial glutathione (GSH) during lung metastasis, driven by elevated expression of SLC25A39, a mitochondrial GSH transporter. Loss of SLC25A39 impairs metastatic colonization in genetic screens, cell line models, and patient-derived xenografts, without affecting primary tumor growth. Mitochondrial GSH import is specifically required during early colonization and functions independently of its canonical antioxidant role. CRISPR activation screens identified ATF4, a stress-induced transcription factor, as a bypass mechanism that restores metastatic potential in SLC25A39-deficient cells. Mechanistically, SLC25A39 is required for optimal ATF4 activation during metastasis and under hypoxia, linking mitochondrial GSH availability to integrated stress response signaling. These findings identify mitochondrial GSH as a necessary and limiting metabolite for metastatic progression.Significance: Mitochondrial GSH import via SLC25A39 is essential for early metastatic colonization in breast cancer, linking metabolic adaptation to stress response signaling. Targeting this pathway may uncover a therapeutic vulnerability specific to metastasis without affecting primary tumor growth.